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compliance with environmental aspects is the first step to be undertaken by the apparel manufacturers to reduce the environmental footprint. In the Republic of Moldova, the apparel manufacturing industry is based on several international cooperation practices, which leads to increased levels of environmental pollution, mainly through the generated waste. The manufacturing processes and the applied technologies increase electricity consumption and generate significant amounts of waste. Obviously, many companies do not know the basic responsibilities and environmental obligations, nor do they know how they can be applied. Under these conditions, the development of proactive practices becomes a natural approach, especially to prevent sanctions for non-compliance with mandatory requirements. The article highlights the steps to be undertaken by the factories to ensure maximum compliance with mandatory requirements imposed by the authorities and the voluntary requirements selected autonomously, in respect to the environmental issues reflected by the legal provisions of the Republic of Moldova harmonized with the European Union law. The authors conducted a qualitative analysis of all requirements and reflected how several apparel factories from the Republic of Moldova apply these pratices in their activities. The results of the analysis provide valuable and useful insights for application and will generate several beneficial effects, such as awareness and compliance with environmental issues, control of economic activity in terms of environmental impact, and confidence to create and provide sustainable value to stakeholders. The presented materials provide a framework through which apparel manufacturers in the Republic of Moldova will take responsibility for their contribution and impact on the ecosystem in which they operate.

Abstract We study the dynamic orbit about Phobos of the Martian Moon eXploration (MMX) spacecraft and simulate gravity field estimation using Doppler, image landmarks, and LIght Detection And Ranging (LIDAR) data based on a mission plan of MMX and investigate whether the differences in the internal density structure of Phobos can be detected through this mission. Degree 2 Stokes coefficients of the Phobos gravity field, $${\overline{C} }_{20}$$ C ¯ 20 and $${\overline{C} }_{22}$$ C ¯ 22 , which are necessary to obtain the moment of inertia by combining with the libration amplitude, could be determined with an accuracy within the order of 0.1% using datasets from two-dimensional (2D) quasi-satellite orbits (QSOs). If observations from 3D-QSO could be realized at low altitude, coefficients up to degree and order 5 could be estimated, which could be used to detect regional density anomalies. Moreover, the observation data from the ascending trajectory after landing on the Phobos surface can be used to detect local density anomalies around the landing site, which could help interpret the origin of the samples and understand the internal structure of Phobos. Graphical Abstract

Abstract Introduction External bleeding is the leading cause of preventable trauma-related death. In certain circumstances, tourniquet application over clothing may be necessary. Therefore, the aim of this study was to assess the effectiveness of tourniquets over different clothing setups. Methods Three windlass tourniquets (CAT, SAMXT, SOFTT-W) were applied over nine different clothing setups and without clothing on the Hapmed™ Tourniquet Trainer. We compared each tourniquet in each clothing setup to the tourniquet trainer that was not dressed, and we compared the three tourniquets within each clothing setup concerning blood loss, applied pressure and application time. Regression analysis of the effect of thickness, mean weight, mean deformation, application time, and applied pressure on blood loss was performed. Results Although blood loss was significantly greater in the CAT and SAMXT tourniquets when they were applied over leather motorcycle trousers, the overall findings showed that the clothing setups significantly reduced or did not affect blood loss. The mean blood loss was the lowest with CAT and the highest with SOFTT-W. The measured mean pressures were lower than 180 mmHg in four out of nine clothing setups with SOFTT-W, but CAT and SAMXT always exceeded this threshold. CAT had the fastest application time. Blood loss was significantly influenced by applied pressure and application time but was influenced to a far lesser degree by clothing parameters. Conclusion The effects of the clothing setups were of little clinical relevance, except for leather motorcycle trousers. The effects of rugged protective equipment, e.g., hazard suits, are conceivable and need to be tested for specific garments with the tourniquet intended for use. No clothing parameter for predicting tourniquet effectiveness could be identified.

Abstract Background The qualities of trainees play a key role in entrustment decisions by clinical supervisors for the assignments of professional tasks and levels of supervision. A recent body of qualitative research has shown that in addition to knowledge and skills, a number of personality traits are relevant in the workplace; however, the relevance of these traits has not been investigated empirically. The aim of this study was to analyse the workplace performance of final-year medical students using an Entrustable Professional Activity (EPA) framework in relation to their personality traits. Methods Medical students at the end of their final clerkship year were invited to participate in an online survey-based, cross-sectional field study. In the survey, the workplace performance was captured using a framework consisting of levels of experienced supervision and a defined set of 12 end-of-undergraduate medical training EPAs. The Big Five personality traits (extraversion, agreeableness, conscientiousness, neuroticism, and openness) of the participating medical students were measured using the Big Five Inventory-SOEP (BFI-S), which consists of 15 items that are rated on a seven-point Likert scale. The data were analysed using descriptive and inferential statistics. Results The study included 880 final-year medical students (mean age: 27.2 years, SD = 3.0; 65% female). The levels of supervision under which the final-year clerkship students carried out the EPAs varied considerably. Significant correlations were found between the levels of experienced supervision and all Big Five dimensions The correlations with the dimensions of extraversion, agreeableness, conscientiousness and openness were positive, and that for the neuroticism dimension was negative (range r = 0.17 to r = − 0.23). Multiple regression analyses showed that the combination of the Big Five personality traits accounted for 0.8–7.5% of the variance in supervision levels on individual EPAs. Conclusions Using the BFI-S, we found that the levels of supervision on a set of end-of-undergraduate medical training EPAs were related to the personality traits of final-year medical students. The results of this study confirm the existing body of research on the role of conscientiousness and extraversion in entrustment decision-making and, in particular, add the personality trait of neuroticism as a new and relevant trainee quality to be considered.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with an urgent unmet clinical need for new therapies. Using a combination of in vitro assays and in vivo preclinical models we demonstrate that therapeutic inhibition of the IGF signalling axis promotes the accumulation of CD8+ cytotoxic T cells within the tumour microenvironment of PDAC tumours. Mechanistically, we show that IGF blockade promotes macrophage and fibroblast production of the chemokines CXCL9 and CXCL10 to facilitate CD8+ T cell recruitment and trafficking towards the PDAC tumour. Exploring this pathway further, we show that IGF inhibition leads to increased STAT1 transcriptional activity, correlating with a downregulation of the AKT/STAT3 signalling axis, in turn promoting Cxcl9 and Cxcl10 gene transcription. Using patient derived tumour explants, we also demonstrate that our findings translate into the human setting. PDAC tumours are frequently described as “immunologically cold”, therefore bolstering CD8+ T cell recruitment to PDAC tumours through IGF inhibition may serve to improve the efficacy of immune checkpoint inhibitors which rely on the presence of CD8+ T cells in tumours.

Analyses of inequalities related to prevention and cancer therapeutics/care show disparities between countries with different economic standing, and within countries with high Gross Domestic Product. The development of basic technological and biological research provides clinical and prevention opportunities that make their implementation into healthcare systems more complex, mainly due to the growth of Personalized/Precision Cancer Medicine (PCM). Initiatives like the USA‐Cancer Moonshot and the EU‐Mission on Cancer and Europe's Beating Cancer Plan are initiated to boost cancer prevention and therapeutics/care innovation and to mitigate present inequalities. The conference organized by the Pontifical Academy of Sciences in collaboration with the European Academy of Cancer Sciences discussed the inequality problem, dependent on the economic status of a country, the increasing demands for infrastructure supportive of innovative research and its implementation in healthcare and prevention programs. Establishing translational research defined as a coherent cancer research continuum is still a challenge. Research has to cover the entire continuum from basic to outcomes research for clinical and prevention modalities. Comprehensive Cancer Centres (CCCs) are of critical importance for integrating research innovations to preclinical and clinical research, as for ensuring state‐of‐the‐art patient care within healthcare systems. International collaborative networks between CCCs are necessary to reach the critical mass of infrastructures and patients for PCM research, and for introducing prevention modalities and new treatments effectively. Outcomes and health economics research are required to assess the cost‐effectiveness of new interventions, currently a missing element in the research portfolio. Data sharing and critical mass are essential for innovative research to develop PCM. Despite advances in cancer research, cancer incidence and prevalence is growing. Making cancer research infrastructures accessible for all patients, considering the increasing inequalities, requires science policy actions incentivizing research aimed at prevention and cancer therapeutics/care with an increased focus on patients' needs and cost‐effective healthcare.

Forest structure, notably the canopy height above the ground, can be obtained from the full-waveform data acquired by satellite laser altimetry. On sloped terrain, the laser pulse can simultaneously reflect from both the vegetation and the ground within their intersecting vertical extents, causing their signals to overlap. This overlap complicates the separation of canopy and ground in the analysis. Consequently, accurately obtaining canopy height and its variation, while considering the influence of terrain factors, poses a significant challenge.In this paper, to counter this, we introduce an innovative approach to remove terrain effects for more reliable identification of canopy and ground. Overlapping footprints from the Ice, Cloud, and land Elevation Satellite (ICESat)/Geoscience Laser Altimeter System (GLAS) and Global Ecosystem Dynamics Investigation (GEDI) campaigns are extracted as coincidental observations. Utilizing the different footprint sizes and by minimizing the center and width of each decomposed Gaussian component pair, optimized ground returns can be obtained. Validation using airborne LiDAR data from the Bartlett Experimental Forest, New Hampshire, USA, indicate that the proposed approach can reduce the ground elevation root-mean-square error (RMSE) by approximately 3 m, compared to the prevalent methods and standard products. While the GEDI product algorithms exhibit a certain accuracy in canopy height retrieval, the proposed approach presents a more constrained error band, signifying less impact from ground elevation discrepancies.While the proposed method enhances canopy height precision, its reliance on overlapping footprints means sacrificing some observations. However, the proposed method is effective in scenarios such as change detection that require repeat observations. As a case study, we applied the proposed method in Porto Velho, Rondônia, Brazil, which is a deforestation hotspot. Using the GlobeLand30 dataset, we investigated the land-cover dynamics from co-located laser footprints, identifying significant forest loss areas and validating our findings with the Hansen Global Forest Change dataset, achieving an accuracy of 83.81 %.In conclusion, this research emphasizes the significance of terrain topography effects in vegetation structure analysis, and positions satellite laser altimetry as instrumental for forest monitoring.

Abstract Quasi-bound states in the continuum (QBICs) coupling into the propagating spectrum manifest themselves as high-quality factor (Q) modes susceptible to perturbations. This poses a challenge in predicting stable Fano resonances for realistic applications. Besides, where and when the maximum field enhancement occurs in real acoustic devices remains elusive. In this work, we theoretically predict and experimentally demonstrate the existence of a Friedrich-Wintgen BIC in an open acoustic cavity. We provide direct evidence for a QBIC by mapping the pressure field inside the cavity using a Laser Doppler Vibrometer (LDV), which provides the missing field enhancement data. Furthermore, we design a symmetry-reduced BIC and achieve field enhancement by a factor of about three compared to the original cavity. LDV measurements are a promising technique for obtaining high-Q modes’ missing field enhancement data. The presented results facilitate the future applications of BICs in acoustics as high-intensity sound sources, filters, and sensors.

Oncolytic viruses are engineered to selectively kill tumor cells and have demonstrated promising results in early-phase clinical trials. To further modulate the innate and adaptive immune system, we generated AZD4820, a vaccinia virus engineered to express interleukin-12 (IL-12), a potent cytokine involved in the activation of natural killer (NK) and T cells and the reprogramming of the tumor immune microenvironment. Testing in cultured human tumor cell lines demonstrated broad in vitro oncolytic activity and IL-12 transgene expression. A surrogate virus expressing murine IL-12 demonstrated antitumor activity in both MC38 and CT26 mouse syngeneic tumor models that responded poorly to immune checkpoint inhibition. In both models, AZD4820 significantly upregulated interferon-gamma (IFN-γ) relative to control mice treated with oncolytic vaccinia virus (VACV)-luciferase. In the CT26 study, 6 of 10 mice had a complete response after treatment with AZD4820 murine surrogate, whereas control VACV-luciferase–treated mice had 0 of 10 complete responders. AZD4820 treatment combined with anti–PD-L1 blocking antibody augmented tumor-specific T cell immunity relative to monotherapies. These findings suggest that vaccinia virus delivery of IL-12, combined with immune checkpoint blockade, elicits antitumor immunity in tumors that respond poorly to immune checkpoint inhibitors.

Summary: Termite-built topology is complex due to group interactions and environmental feedback. Being interlinked with material characteristics and related to functionality, an accurate synthesis of termite mound topology has never been achieved. We scanned inner termite mound pieces via high-resolution micro-computed tomography. A wavelet scattering transform followed by optimization extracts features that are fed into a Gaussian Random Fields (GRFs) approach to synthesize termite-mimetic spinodal topology. Compared to natural structures the GRF topology is more regular. Irregularity is related to anisotropy, indicative of directionality caused by porous network connectivity of chambers and corridors. Since GRFs are related to diffusion, we assume that deterministic behavioral traits play a significant role in the development of these local differences. We pioneer a framework to reliably mimic termite mound spinodal features. Engineering termite-inspired structures will allow to inspect aspects of termite architectures and their behavior to manufacture novel material concepts with imprinted multi-functionality.

European cancer research stakeholders met in October 2022 in Heidelberg, Germany, at the 5th Gago conference on European Cancer Policy, to discuss the current cancer research and cancer care policy landscape in Europe. Meeting participants highlighted gaps in the existing European programmes focusing on cancer research, including Europe's Beating Cancer Plan (EBCP), the Mission on Cancer (MoC), Understanding Cancer (UNCAN.eu), and the joint action CRANE, and put forward the next priorities, in the form of the Heidelberg Manifesto for cancer research. This meeting report presents all discussions that shed light on how infrastructures can be effectively shaped for translational, prevention, clinical and outcomes cancer research, with a focus on implementation and sustainability and while engaging patients and the public. In addition, we summarize recommendations on how to introduce frameworks for the digitalization of European cancer research. Finally, we discuss what structures, commitment, and resources are needed to establish a collaborative cancer research environment in Europe to achieve the scale required for innovation.

ABSTRACTCold weather warfare is of increasing importance. Haemorrhage is the most common preventable cause of death in military conflicts. We analysed the pressure of the Combat Application Tourniquet® Generation 7 (CAT), the SAM® Extremity Tourniquet (SAMXT) and the SOF® Tactical Tourniquet Wide Generation 4 (SOFTT) over different military cold weather clothing setups with a leg tourniquet trainer. We conducted a selective PubMed search and supplemented this with own experiences in cold weather medicine. The CAT and the SAMXT both reached the cut off value of 180mmHg in almost all applications. The SOFTT was unable to reach the 180mmHg limit in less than 50% of all applications in some clothing setups. We outline the influence of cold during military operations by presenting differences between military and civilian cold exposure. We propose a classification of winter warfare and identify caveats and alterations of Tactical Combat Casualty Care in cold weather warfare, with a special focus on control of bleeding. The application of tourniquets over military winter clothing is successful in principle, but effectiveness may vary for different tourniquet models. Soldiers are more affected and impaired by cold than civilians. Military commanders must be made aware of medical alterations in cold weather warfare.

In order to recover from infection, organisms must balance robust immune responses to pathogens with the tolerance of immune-mediated pathology. This balance is particularly critical within the central nervous system, whose complex architecture, essential function, and limited capacity for self-renewal render it susceptible to both pathogen- and immune-mediated pathology. Here, we identify the alarmin IL-33 and its receptor ST2 as critical for host survival to neuroinvasive flavivirus infection. We identify oligodendrocytes as the critical source of IL-33, and microglia as the key cellular responders. Notably, we find that the IL-33/ST2 axis does not impact viral control or adaptive immune responses; rather, it is required to promote the activation and survival of microglia. In the absence of intact IL-33/ST2 signaling in the brain, neuroinvasive flavivirus infection triggered aberrant recruitment of monocyte-derived peripheral immune cells, increased neuronal stress, and neuronal cell death, effects that compromised organismal survival. These findings identify IL-33 as a critical mediator of CNS tolerance to pathogen-initiated immunity and inflammation.

A decision model is developed by adopting two control techniques, combining cultural methods and pesticides in a hybrid approach. To control the adverse effects in the long term and to be able to evaluate the extensive use of pesticides on the environment and nearby ecosystems, the novel decision model assumes the use of pesticides only in an emergency situation. We, therefore, formulate a rice-pest-control model by rigorously modelling a rice-pest system and including the decision model and control techniques. The model is then extended to become an optimal control system with an objective function that minimizes the annual losses of rice by controlling insect pest infestations and simultaneously reduce the adverse impacts of pesticides on the environment and nearby ecosystems. This rice-pest-control model is verified by analysis, obtains the necessary conditions for optimality, and confirms our main results numerically. The rice-pest system is verified by stability analysis at equilibrium points and shows transcritical bifurcations indicative of acceptable thresholds for insect pests to demonstrate the pest control strategy.

Repeated high-resolution imaging has revealed current mass wasting in the form of ice block falls at steep scarps of Mars. However, both the accuracy and efficiency of ice-fragments’ detection are limited when using conventional computer vision methods. Existing deep learning methods suffer from the problem of shadow interference and indistinguishability between classes. To address these issues, we proposed a deep learning-driven change detection model that focuses on regions of interest. A convolutional neural network simultaneously analyzed bitemporal images, i.e., pre- and postdetach images. An augmented attention module was integrated in order to suppress irrelevant regions such as shadows while highlighting the detached ice-fragments. A combination of dice loss and focal loss was introduced to deal with the issue of imbalanced classes and hard, misclassified samples. Our method showed a true positive rate of 84.2% and a false discovery rate of 16.9%. Regarding the shape of the detections, the pixel-based evaluation showed a balanced accuracy of 85% and an F1 score of 73.2% for the detached ice-fragments. This last score reflected the difficulty in delineating the exact boundaries of some events both by a human and the machine. Compared with five state-of-the-art change detection methods, our method can achieve a higher F1 score and surpass other methods in excluding the interference of the changed shadows. Assessing the detections of the detached ice-fragments with the help of previously detected corresponding shadow changes demonstrated the capability and robustness of our proposed model. Furthermore, the good performance and quick processing speed of our developed model allow us to efficiently study large-scale areas, which is an important step in estimating the ongoing mass wasting and studying the evolution of the martian polar scarps.

This research was focused on innovative design of lattice metamaterials that can exhibit tunable double-negative mechanical properties and elastic isotropy simultaneously. A discrete topology optimization method using a multi-material ground structure was developed to create microlattices exhibiting both negative thermal expansion coefficient and negative Poisson’s ratio in a single integrated design, while maintaining elastic isotropy. First, the numerical homogenization method with beam elements was used to estimate the effective thermal and elastic properties of a microlattice. Second, the topological design, subject to required geometric constraints, was formulated as a mixed integer programming problem to discover a series of multi-material microlattices that present customized isotropic values of negative thermal expansion coefficient and negative Poisson’s ratio. Finally, several three-dimensional multi-material microstructures were produced by altering either the cross-sections or constituent materials of struts to demonstrate their tunable mechanical properties.

High-resolution Digital Terrain Models (DTMs) of the lunar surface can provide crucial spatial information for lunar exploration missions. In this paper, we propose a method to generate high-quality DTMs based on a synthesis of deep learning and Shape from Shading (SFS) with a Lunar Reconnaissance Orbiter Narrow Angle Camera (LROC NAC) image as well as a coarse-resolution DTM as input. Specifically, we use a Convolutional Neural Network (CNN)-based deep learning architecture to predict initial pixel-resolution DTMs. Then, we use SFS to improve the details of DTMs. The CNN-model is trained based on the dataset with 30, 000 samples, which are formed by stereo-photogrammetry derived DTMs and orthoimages using LROC NAC images as well as the Selenological and Engineering Explorer and LRO Elevation Model (SLDEM). We take Chang’E-3 landing site as an example, and use a 1.6 m resolution LROC NAC image and 5 m resolution stereo-photogrammetry derived DTM as input to test the proposed method. We evaluate our DTMs with those from stereo-photogrammetry and deep learning. The result shows the proposed method can generate 1.6 m resolution high-quality DTMs, which can clearly improve the visibility of details of the initial DTM generated from the deep learning method.

Abstract Background Acquiring medical knowledge is a key competency for medical students and a lifelong requirement for physicians. Learning techniques can improve academic success and help students cope with stressors. To support students’ learning process medical faculties should know about learning techniques. The purpose of this study is to analyse the preferred learning techniques of female and male as well as junior and senior medical students and how these learning techniques are related to perceived learning difficulties. Methods In 2019, we conducted an online survey with students of the undergraduate, competency-based curriculum of medicine at Charité – Universitätsmedizin Berlin. We chose ten learning techniques of high, moderate and low utility according to Dunlosky et al. (2013) and we asked medical students to rate their preferred usage of those techniques using a 5-point Likert scale. We applied t-tests to show differences in usage between female and male as well as junior and senior learners. Additionally, we conducted a multiple regression analysis to explore the predictive power of learning techniques regarding perceived difficulties. Results A total of 730 medical students (488 women, 242 men, Mage = 24.85, SD = 4.49) use three techniques the most: ‘highlighting’ (low utility), ‘self-explanation’ (moderate utility) and ‘practice testing’ (high utility). Female students showed a significantly higher usage of low-utility learning techniques (t(404.24) = -7.13, p

Objective: Type 1 diabetes (T1D) is characterized by autoimmune-associated β-cell loss, insulin insufficiency, and hyperglycemia. Although TNFα signaling is associated with β-cell loss and hyperglycemia in non-obese diabetic mice and human T1D, the molecular mechanisms of β-cell TNF receptor signaling have not been fully characterized. Based on work in other cell types, we hypothesized that receptor interacting protein kinase 1 (RIPK1) and receptor interacting protein kinase 3 (RIPK3) regulate TNFα-induced β-cell death in concert with caspase activity. Methods: We evaluated TNFα-induced cell death, caspase activity, and TNF receptor pathway molecule expression in immortalized NIT-1 and INS-1 β-cell lines and primary mouse islet cells in vitro. Our studies utilized genetic and small molecule approaches to alter RIPK1 and RIPK3 expression and caspase activity to interrogate mechanisms of TNFα-induced β-cell death. We used the β-cell toxin streptozotocin (STZ) to determine the susceptibility of Ripk3+/+ and Ripk3−/− mice to hyperglycemia in vivo. Results: Expression of TNF receptor signaling molecules including RIPK1 and RIPK3 was identified in NIT-1 and INS-1 β cells and isolated mouse islets at the mRNA and protein levels. TNFα treatment increased NIT-1 and INS-1 cell death and caspase activity after 24–48 h, and BV6, a small molecule inhibitor of inhibitor of apoptosis proteins (IAPs) amplified this TNFα-induced cell death. RIPK1 deficient NIT-1 cells were protected from TNFα- and BV6-induced cell death and caspase activation. Interestingly, small molecule inhibition of caspases with zVAD-fmk (zVAD) did not prevent TNFα-induced cell death in either NIT-1 or INS-1 cells. This caspase-independent cell death was increased by BV6 treatment and decreased in RIPK1 deficient NIT-1 cells. RIPK3 deficient NIT-1 cells and RIPK3 kinase inhibitor treated INS-1 cells were protected from TNFα+zVAD-induced cell death, whereas RIPK3 overexpression increased INS-1 cell death and promoted RIPK3 and MLKL interaction under TNFα+zVAD treatment. In mouse islet cells, BV6 or zVAD treatment promoted TNFα-induced cell death, and TNFα+zVAD-induced cell death was blocked by RIPK3 inhibition and in Ripk3−/− islet cells in vitro. Ripk3−/− mice were also protected from STZ-induced hyperglycemia and glucose intolerance in vivo. Conclusions: RIPK1 and RIPK3 regulate TNFα-induced β-cell death in concert with caspase activity in immortalized and primary islet β cells. TNF receptor signaling molecules such as RIPK1 and RIPK3 may represent novel therapeutic targets to promote β-cell survival and glucose homeostasis in T1D.

Cu-to-Cu thermal compression bonding (TCB) has emerged as a promising solution for ultrafine pitch packaging in 3D integrated circuit technologies. Despite the progress made by conventional Cu-to-Cu TCB methods in achieving good mechanical strength of the Cu bonds, the bonding processes generally require high temperature and high pressure, which may degrade the performance and reliability of the device. Therefore, it is imperative to investigate the processing parameters to understand the bonding mechanism and achieve effective TCB at a low temperature and low pressure. Here, we developed an in situ TCB technique inside a scanning electron microscope. The in situ TCB method enables a real-time observation of bonding development, which provides critical insights into how the texture and microstructure of Cu bumps may influence the creep and surface diffusion during the bonding process. This work features a strategy to advance our understanding of the bonding mechanisms and provides insight into tailoring the microstructure of Cu for bonding at a low temperature and low pressure.

Acoustic momentum exchange between objects and the surrounding fluid can be quantified in terms of acoustic radiation force and torque, and depends on several factors including the objects’ geometries. For a one-dimensional plane wave type, the induced torque on the objects with arbitrary shape becomes a function of both, direct polarization and Willis coupling, as a result of shape asymmetry, and has only in-plane components. Here, we investigate, in the Rayleigh scattering limit, the momentum transfer to objects in the non-planar pressure field of an acoustic Bessel beam with axisymmetric wave front. This type of beam is selected since it can be practically realized by an array of transducers that are cylindrically arranged and tilted at the cone angle β which is a proportionality index of the momentum distribution in the transverse and axial propagation directions. The analytical expressions of the radiation force and torque are derived for both symmetric and asymmetric objects. We show the dependence of radiation force and torque on the characteristic parameters β and radial distance from the beam axis. By comparing against the case of a plane travelling plane wave, zero β angle, we demonstrated that the non-planar wavefront of a zeroth order Bessel beam causes an additional radial force and axial torque. We also show that, due to Willis coupling, an asymmetric object experiences greater torques in the θ direction, by minimum of one order of magnitude compared to a plane travelling wave. Further, the components of the partial torques owing to direct polarization and Willis coupling act in the same direction, except for a certain range of cone angle β. Our findings show that a non-planar wavefront, which is quantified by β in the case of a zeroth-order Bessel beam, can be used to control the magnitude and direction of the acoustic radiation force and torque acting on arbitrarily shaped objects, implying that the wavefront should be adjusted according to the object’s shape to impart acoustic momentum in all directions and achieve a desired acoustophoretic response.

Our goal is to request input from the lunar and planetary community regarding issues of planetary coordinate systems and cartography standards. We begin with an overview of the work of the International Astronomical Union Working Group on Cartographic Coordinates and Rotational Elements. We briefly describe the operations and membership of the Working Group, some of the various uses of the recommendations it makes, our most recent (2018) published report and the recommendations therein, and the outlook for our next such report. We then consider several issues and questions regarding the future of the Working Group and regarding planetary cartography and planetary data spatial infrastructure in general. This includes possible near-term projects, how we and others might collect and consider community input and includes some ideas regarding possible outcomes or future work that will need to be addressed by the Working Group or other organizations.

This paper presents a review of lunar topographic mapping in the two decades of the 21st century, including descriptions of lunar exploration missions, relevant payloads and data, mapping techniques, as well as global and regional mapping products. Various lunar photogrammetric mapping techniques such as construction of geometric models of lunar orbital images, block adjustments, shape from shading, co-registration of lunar orbital image and elevation data have been developed to process lunar orbital images and generate mapping products. Global topographic products at hectometer and decameter scales have been produced from orbital images and/or laser altimeter data. Regional topographic maps of the landing sites and other sites of interest have been generated at meter-scale using the sub-meter to meter resolution orbital images. Detailed local topographic products at centimeter to millimeter scales of the landing sites and rover traverse areas have been produced using descent images acquired by the landers and stereo images acquired by the rovers. These multiple-scale topographic mapping products have been extensively used to support various science applications, as well as engineering applications such as surface operations of the rovers.

A comprehensive translational cancer research approach focused on personalized and precision medicine, and covering the entire cancer research–care–prevention continuum has the potential to achieve in 2030 a 10‐year cancer‐specific survival for 75% of patients diagnosed in European Union (EU) member states with a well‐developed healthcare system. Concerted actions across this continuum that spans from basic and preclinical research through clinical and prevention research to outcomes research, along with the establishment of interconnected high‐quality infrastructures for translational research, clinical and prevention trials and outcomes research, will ensure that science‐driven and social innovations benefit patients and individuals at risk across the EU. European infrastructures involving comprehensive cancer centres (CCCs) and CCC‐like entities will provide researchers with access to the required critical mass of patients, biological materials and technological resources and can bridge research with healthcare systems. Here, we prioritize research areas to ensure a balanced research portfolio and provide recommendations for achieving key targets. Meeting these targets will require harmonization of EU and national priorities and policies, improved research coordination at the national, regional and EU level and increasingly efficient and flexible funding mechanisms. Long‐term support by the EU and commitment of Member States to specialized schemes are also needed for the establishment and sustainability of trans‐border infrastructures and networks. In addition to effectively engaging policymakers, all relevant stakeholders within the entire continuum should consensually inform policy through evidence‐based advice.

This article is an update of the requirements of a specialist breast centre, produced by EUSOMA and endorsed by ECCO as part of Essential Requirements for Quality Cancer Care (ERQCC) programme, and ESMO.To meet aspirations for comprehensive cancer control, healthcare organisations must consider the requirements in this article, paying particular attention to multidisciplinarity and patient-centred pathways from diagnosis, to treatment, to survivorship. • The centrepiece of this article is the requirements section, comprising definitions; multidisciplinary structure; minimum case, procedure and staffing volumes; and detailed descriptions of the skills of, and resources needed by, members and specialisms in the multidisciplinary team in a breast centre. • These requirements are positioned within narrative on European breast cancer epidemiology, the standard of care, challenges to delivering this standard, and supporting evidence, to enable a broad audience to appreciate the importance of establishing these requirements in specialist breast centres.

Silk from silkworms and spiders is an exceptionally important natural material, inspiring a range of new products and applications due to its high strength, elasticity, and toughness at low density, as well as its unique conductive and optical properties. Transgenic and recombinant technologies offer great promise for the scaled-up production of new silkworm- and spider-silk-inspired fibres. However, despite considerable effort, producing an artificial silk that recaptures the physico-chemical properties of naturally spun silk has thus far proven elusive. The mechanical, biochemical, and other properties of pre-and post-development fibres accordingly should be determined across scales and structural hierarchies whenever feasible. We have herein reviewed and made recommendations on some of those practices for measuring the bulk fibre properties; skin-core structures; and the primary, secondary, and tertiary structures of silk proteins and the properties of dopes and their proteins. We thereupon examine emerging methodologies and make assessments on how they might be utilized to realize the goal of developing high quality bio-inspired fibres.

Abstract Background The safety, efficacy, pharmacokinetics, and pharmacodynamics of the anti-programmed cell death-1 antibody MEDI0680 were evaluated in a phase I, multicenter, dose-escalation study in advanced solid malignancies. Methods MEDI0680 was administered intravenously once every 2 weeks (Q2W) or once every 3 weeks at 0.1, 0.5, 2.5, 10 or 20 mg/kg. Two cohorts received 20 mg/kg once a week for 2 or 4 weeks, then 20 mg/kg Q2W. All were treated for 12 months or until progression. The primary endpoint was safety. Secondary endpoints were efficacy and pharmacokinetics. Exploratory endpoints included pharmacodynamics. Results Fifty-eight patients were treated. Median age was 62.5 years and 81% were male. Most had kidney cancer (n = 36) or melanoma (n = 9). There were no dose-limiting toxicities. Treatment-related adverse events occurred in 83% and were grade ≥ 3 in 21%. Objective clinical responses occurred in 8/58 patients (14%): 5 with kidney cancer, including 1 with a complete response, and 3 with melanoma. The relationship between dose and serum levels was predictable and linear, with apparent receptor saturation at 10 mg/kg Q2W and all 20 mg/kg cohorts. Conclusions MEDI0680 induced peripheral T-cell proliferation and increased plasma IFNγ and associated chemokines regardless of clinical response. CD8+ T-cell tumor infiltration and tumoral gene expression of IFNG, CD8A, CXCL9, and granzyme K (GZMK) were also increased following MEDI0680 administration. Trial registration NCT02013804; date of registration December 12, 2013.

The TU Berlin group of the Lunar Reconnaissance Orbiter Camera (LROC) team has implemented a Bundle Adjustment (BA) for spaceborne multi-lenses line scan imagers, by rigorously modeling the geometric properties of the image acquisition. The BA was applied to stereo image sets of the LROC Narrow Angle Camera (NAC) and first results show, that the overall geometry of the stereo models were significantly improved. Ray intersection accuracies of initially up to several meters were homogenized within the integrated stereo models and improved to 0.14 m on average. The mean point error of the adjusted 3D object points was estimated by the BA to be 0.95 m. The inclusion of available Lunar Orbiter Laser Altimeter (LOLA) shots as 3D ground control to the BA, accurately tied to the image space by an aforegoing co-registration, allowed to register the final adjusted NAC DTM to the currently most accurate global lunar reference frame. The BA also provides accuracy assessments of the individual LOLA tracks used for georeference during the adjustment, which will be useful to further assess LOLA derived products.

We map lateral variations in bulk density of the upper lunar highland crust using the most recent GRAIL gravity field solution of degree and order 1500 in combination with LOLA topography data, both truncated to an upper limit of degree and order 700. Our maps have a spatial resolution of 0.75°, where each grid point was calculated using circular analysis regions of 3° radius. We apply two methods, which yield similar results for most parts of the study area. The first method minimizes the correlation between topography and Bouguer anomalies, the second maximizes the smoothness of the Bouguer anomalies. Both approaches suffer in the case that terrain is flat and lacks topographic features; consequently, this is where results from the two methods differ. We also mapped porosity of the crust using grain densities derived from Lunar Prospector spectrometry and sample analysis. It appears that variations in bulk density are mostly related to differences in crustal porosity. We find that high porosity is often associated with areas of impact basins. This confirms earlier studies, that impacts changed the geophysical characteristics of the lithosphere sustainably and that the high porosity of the upper lunar crust is most likely impact induced.

Comprehensive cancer centres (CCCs) are at the heart of the landscape of cancer research, education and care in Europe. They are vital hubs where the historic gaps in the research to clinical care continuum are bridged. CCCs have established hallmarks, but a greater emphasis is needed in Europe to create more effective CCCs using the partnership model of university medical centres and university research departments and institutes. This review will summarise the organisational structures and processes essential for producing quality outcomes for patients and effectiveness in the translational process. The Organisation of European Cancer Institutes and European Academy of Cancer Sciences have established complementary quality accreditations systems to test the clinical and research excellence of CCCs. The EU should have an ambition to create more CCCs based on university hospitals, for each 5–10 million population and in every Member State.

Preclinical studies of PD-L1 and CTLA-4 blockade have relied heavily on mouse syngeneic tumor models with intact immune systems, which facilitate dissection of immunosuppressive mechanisms in the tumor microenvironment. Commercially developed monoclonal antibodies (mAbs) targeting human PD-L1, PD-1, and CTLA-4 may not demonstrate cross-reactive binding to their mouse orthologs, and surrogate anti-mouse antibodies are often used in their place to inhibit these immune checkpoints. In each case, multiple choices exist for surrogate antibodies, which differ with respect to species of origin, affinity, and effector function. To develop relevant murine surrogate antibodies for the anti-human PD-L1 mAb durvalumab and the anti-human CTLA-4 mAb tremelimumab, rat/mouse chimeric or fully murine mAbs engineered for reduced effector function were developed and compared with durvalumab and tremelimumab. Characterization included determination of target affinity, in vivo effector function, pharmacokinetic profile, and anti-tumor efficacy in mouse syngeneic tumor models. Results showed that anti–PD-L1 and anti–CTLA-4 murine surrogates with pharmacologic properties similar to those of durvalumab and tremelimumab demonstrated anti-tumor activity in a subset of commonly used mouse syngeneic tumor models. This activity was not entirely dependent on antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis effector function, or regulatory T-cell depletion, as antibodies engineered to lack these features showed activity in models historically sensitive to checkpoint inhibition, albeit at a significantly lower level than antibodies with intact effector function.

The Mars Orbiter Laser Altimeter (MOLA) Precision Experiment Data Records (PEDR) serve as the geodetic reference of Mars. However, these MOLA footprints were geolocated using outdated auxiliary information that dates back to 2003. In this study, we recompute the MOLA PEDR footprint locations and investigate the impact of the updated spacecraft orbit model and Mars rotational model on MOLA’s geolocation. We observe quasi-exponential increases near the poles of up to 30 m in the recomputation residuals for the nadir profiles. Meanwhile, we demonstrate that limitations exist in the stored MOLA PEDR attitude records, which can shift the footprint up to hundreds of meters laterally and several meters radially. The usage of the Navigation and Ancillary Information Facility (NAIF)-archived attitude information instead can circumvent this issue and avoid the approximation errors due to discrete samplings of the attitude information used in geolocation by the PEDR dataset. These approximation errors can be up to 60 m laterally and 1 m radially amid controlled spacecraft maneuvers. Furthermore, the incorporation of the updated spacecraft orbit and Mars rotational model can shift the MOLA profiles up to 200 m laterally and 0.5 m radially, which are much larger in magnitude than the aforementioned dramatic increases near the poles. However, the shifted locations of the reprocessed profiles are significantly inconsistent with the PEDR profiles after the global cross-over analysis.

The excessive, indiscriminate, and continued use of anthelmintic drugs as control methods favors parasite resistance, and this phenomenon has been reported in Brazil and worldwide. The current status of parasite resistance to anthelmintic drugs in sheep flocks in Rio Grande do Sul was assessed by calculating the EPG count in the stool to estimate the prevalence of resistance to the anthelmintic drugs closantel, levamisole, fenbendazole, monepantel, and moxidectin in seven properties. The animals from each flock were randomly distributed in six groups according to the anthelminthic drug used, as follows: T1, levamisole; T2, fenbendazole; T3, monepantel; T4, moxidectin; T5, closantel; and T6, control. On day zero, fecal samples were collected, and each animal was treated with one anthelminthic drug. Fecal samples were collected again after 14 days to calculate the efficacy of each active principle. Coproculture was performed using a pool of fecal samples from each group on day 0 and 14 to identify the predominant genera and prevalence of helminths. The genera identified in the coprocultures were Haemonchus, Trichostrongylus, Oesophagostomum, and Teladorsagia. All flocks developed resistance to levamisole, fenbendazole, moxidectin, and closantel. Moreover, resistance to monepantel was found in four of the seven farms. These results demonstrate the critical situation of anthelmintic resistance in sheep flocks in Rio Grande do Sul and the need to adopt other integrated control measures in addition to anthelmintic treatment.

We present a method that aligns lunar south and north pole LOLA DTMs using selected LOLA tracks and co-registration techniques. The selected LOLA tracks were then co-registered to the aligned polar DTMs with the aim to create a new LOLA frame of high relative accuracy. At the poles the relative accuracy of the resulting LOLA frame improved in comparison with the original LOLA frame, especially at the north pole. At lower latitudes on the lunar near side we could show that we achieve smaller residuals between our LOLA frame and a photogrammetrically derived reference DTM than with the original LOLA frame. On the far side we could not achieve better results which we believe is stemming from the generally less accurate orbit knowledge there. From the aligned polar DTMs we were able to derive a polar radius of 1738,049 km.

A lunar global control network provides geodetic datum and control points for mapping of the lunar surface. The widely used Unified Lunar Control Network 2005 (ULCN2005) was built based on a combined photogrammetric solution of Clementine images acquired in 1994 and earlier photographic data. In this research, we propose an initiative for construction of a new-generation lunar global control network using multi-mission data newly acquired in the 21st century, which have much better resolution and precision than the old data acquired in the last century. The new control network will be based on a combined photogrammetric solution of an extended global image and laser altimetry network. The five lunar laser ranging retro-reflectors, which can be identified in LROC NAC images and have cm level 3D position accuracy, will be used as absolute control points in the least squares photogrammetric adjustment. Recently, a new radio total phase ranging method has been developed and used for high-precision positioning of Chang’e-3 lander; this shall offer a new absolute control point. Systematic methods and key techniques will be developed or enhanced, including rigorous and generic geometric modeling of orbital images, multi-scale feature extraction and matching among heterogeneous multi-mission remote sensing data, optimal selection of images at areas of multiple image coverages, and large-scale adjustment computation, etc. Based on the high-resolution new datasets and developed new techniques, the new generation of global control network is expected to have much higher accuracy and point density than the ULCN2005.

The small (approximately 500 km in diameter) satellite Enceladus is moving near the equatorial plane and deep in the gravity field of its parent planet Saturn. Owing to tidal interaction with its parent, Enceladus has adopted a pronounced 3-axial ellipsoidal shape and is tidally locked, with rotational and orbital periods of about 1.37 days. As the equator of Saturn is inclined to the planet’s orbital plane, Enceladus, like most of the other satellites of Saturn, undergoes pronounced seasons. This paper gives a summary of the current status as well as shortcomings of our current knowledge regarding Enceladus’ geodetic and dynamic parameters.

Some of the most frequently used online applications are Facebook, WhatsApp, and Twitter. These applications allow individuals to communicate with other users, to share information or pictures, and to stay in contact with friends all over the world. However, a growing number of users suffer from negative consequences due to their excessive use of these applications, which can be referred to as Internet-communication disorder. The frequent use and easy access of these applications may also trigger the individual's fear of missing out on content when not accessing these applications. Using a sample of 270 participants, a structural equation model was analyzed to investigate the role of psychopathological symptoms and the fear of missing out on expectancies towards Internet-communication applications in the development of symptoms of an Internet-communication disorder. The results suggest that psychopathological symptoms predict higher fear of missing out on the individual's Internet-communication applications and higher expectancies to use these applications as a helpful tool to escape from negative feelings. These specific cognitions mediate the effect of psychopathological symptoms on Internet-communication disorder. Our results are in line with the theoretical model by Brand et al. (2016) as they show how Internet-related cognitive bias mediates the relationship between a person's core characteristics (e.g., psychopathological symptoms) and Internet-communication disorder. However, further studies should investigate the role of the fear of missing out as a specific predisposition, as well as specific cognition in the online context.

We analyse images taken by the MErcury Surface, Space ENviorment, GEochemistry, and Ranging (MESSENGER) spacecraft for the camera’s thermal response in the harsh thermal environment near Mercury. Specifically, we study thermally induced variations in focal length of the Mercury Dual Imaging System (MDIS). Within the several hundreds of images of star fields, the Wide Angle Camera (WAC) typically captures up to 250 stars in one frame of the panchromatic channel. We measure star positions and relate these to the known star coordinates taken from the Tycho-2 catalogue. We solve for camera pointing, the focal length parameter and two non-symmetrical distortion parameters for each image. Using data from the temperature sensors on the camera focal plane we model a linear focal length function in the form of f(T) = A0 + A1 T. Next, we use images from MESSENGER’s orbital mapping mission. We deal with large image blocks, typically used for the production of a high-resolution digital terrain models (DTM). We analyzed images from the combined quadrangles H03 and H07, a selected region, covered by approx. 10,600 images, in which we identified about 83,900 tiepoints. Using bundle block adjustments, we solved for the unknown coordinates of the control points, the pointing of the camera – as well as the camera’s focal length. We then fit the above linear function with respect to the focal plane temperature. As a result, we find a complex response of the camera to thermal conditions of the spacecraft. To first order, we see a linear increase by approx. 0.0107 mm per degree temperature for the Narrow-Angle Camera (NAC). This is in agreement with the observed thermal response seen in images of the panchromatic channel of the WAC. Unfortunately, further comparisons of results from the two methods, both of which use different portions of the available image data, are limited. If leaving uncorrected, these effects may pose significant difficulties in the photogrammetric analysis, specifically these may be responsible for erroneous longwavelength trends in topographic models.

Summary: Necroptosis is a form of programmed cell death that is defined by activation of the kinase RIPK3 and subsequent cell membrane permeabilization by the effector MLKL. RIPK3 activation can also promote immune responses via production of cytokines and chemokines. How active cytokine production is coordinated with the terminal process of necroptosis is unclear. Here, we report that cytokine production continues within necroptotic cells even after they have lost cell membrane integrity and irreversibly committed to death. This continued cytokine production is dependent on mRNA translation and requires maintenance of endoplasmic reticulum integrity that remains after plasma membrane integrity is lost. The continued translation of cytokines by cellular corpses contributes to necroptotic cell uptake by innate immune cells and priming of adaptive immune responses to antigens associated with necroptotic corpses. These findings imply that cell death and production of inflammatory mediators are coordinated to optimize the immunogenicity of necroptotic cells. : Necroptotic cell death is associated with cytokine production. Orozco et al. show that necroptotic cell “corpses” continue to synthesize cytokines after they have lost membrane integrity and committed to cell death. This activity involves continued mRNA translation and requires ER function that continues after plasma membrane rupture. Keywords: necroptosis, cell death, phagocytosis, cytokines, RIPK3, MLKL

We present a method which is a continuation of work-in-progress paper (Kozlova et al., 2014). LRO NAC DEM, orthomosaic, and the results of detailed studies of the Lunokhod-2 route were used for modeling of individual sites in order to find observation points for archival panoramas. The method suggests determination of rover coordinates from photogrammetry processing of obtained surface images together with artificially modeled synthetic images produced from high-resolution DEM and orthomosaic. We have now tested the method on models and on real Lunokhod-2 data. The method proved its effectiveness on models, however, for Lunokhod-2 panoramas further research is needed to calibrate the camera properly.

A new global control point network was derived for Enceladus, based on Cassini and Voyager-2 image data. Cassini images were taken from 2005 to 2014, for Voyager we have only one flyby in the middle of 1981. We have derived 3D Cartesian coordinates for 1128 control points as well as improved pointing data for 12 Voyager and 193 Cassini images in the Enceladus-fixed coordinate system. The point accuracies vary from 55 m to 2900 m (average point accuracy – 221 m). From tracking of the control points we detect a librational motion described by a model which includes 3 different periods and amplitudes (Rambaux et al., 2011). We determine the amplitudes for each term. Our new control point network has a higher number of point measurements and a higher accuracy than previous data (Giese et al., 2014).

Uso excessivo, indiscriminado e continuado de anti-helmínticos como métodos de controle favorece o desenvolvimento de isolados de parasitos resistentes, fenômeno relatado no Brasil e no mundo. Com o objetivo de verificar a atual situação da resistência anti-helmíntica em rebanhos ovinos no Rio Grande do Sul, foram realizados testes de redução da contagem de OPG nas fezes (TRCOF), a fim de estimar a prevalência de resistência parasitária em sete propriedades utilizando os seguintes anti-helmínticos: closantel, levamisol, fenbendazol, monepantel e moxidectina. Em cada rebanho os animais foram distribuídos aleatoriamente, respeitando a homogeneidade de categorias, em seis grupos, T1 - levamisol, T2 - fenbendazol, T3 - monepantel, T4 - moxidectina, T5 - closantel e T6 - controle. No dia zero foram coletadas amostras de fezes e os animais foram tratados, após 14 dias foi feita nova coleta de fezes para calcular a eficácia de cada princípio ativo. A coprocultura foi realizada através de um pool de fezes de cada grupo no dia 0 e 14 para identificação dos principais gêneros e as suas prevalências. Os gêneros de helmintos identificados nas coproculturas realizadas foram: Haemonchus, Trichostrongylus, Oesophagostomum e Teladorsagia. Em todos os rebanhos foi diagnosticada resistência ao levamisol, febendazol, moxidectina e closantel, e, em quatro das sete propriedades foi encontrada resistência ao monepantel. Alerta-se para a situação crítica da resistência anti-helmíntica nos rebanhos gaúchos e a necessidade de se adotarem outras medidas de controle integrado além do tratamento exclusivo com anti-helmíntico.

Glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) is part of a system of signals involved in controlling T-cell activation. Targeting and agonizing GITR in mice promotes antitumor immunity by enhancing the function of effector T cells and inhibiting regulatory T cells. Here, we describe MEDI1873, a novel hexameric human GITR agonist comprising an IgG1 Fc domain, a coronin 1A trimerization domain and the human GITRL extracellular domain (ECD). MEDI1873 was optimized through systematic testing of different trimerization domains, aglycosylation of the GITRL ECD and comparison of different Fc isotypes. MEDI1873 exhibits oligomeric heterogeneity and superiority to an anti-GITR antibody with respect to evoking robust GITR agonism, T-cell activation and clustering of Fc gamma receptors. Further, it recapitulates, in vitro, several aspects of GITR targeting described in mice, including modulation of regulatory T-cell suppression and the ability to increase the CD8+:CD4+ T-cell ratio via antibody-dependent T-cell cytotoxicity. To support translation into a therapeutic setting, we demonstrate that MEDI1873 is a potent T-cell agonist in vivo in non-human primates, inducing marked enhancement of humoral and T-cell proliferative responses against protein antigen, and demonstrate the presence of GITR- and FoxP3-expressing infiltrating lymphocytes in a range of human tumors. Overall our data provide compelling evidence that MEDI1873 is a novel, potent GITR agonist with the ability to modulate T-cell responses, and suggest that previously described GITR biology in mice may translate to the human setting, reinforcing the potential of targeting the GITR pathway as a therapeutic approach to cancer.

Recently the Lunar Reconnaissance Orbiter (LRO) has obtained images, which cover landing sites from previous missions to the Moon in unprecedented high resolution (up to 0.3 m/pixel). These new data allow us to carry out a precision mapping of the Lunokhod landing sites, combining orbital high resolution images with surface panoramas taken by the rovers during their missions. Unfortunately, a lot of supplementary information about the missions, the rovers and their instrumentation is lost, which includes timing information and exterior orientation parameters. So, we have developed new methods and techniques of Lunokhod panorama processing by means of modern photogrammetric software supported by LRO data

The department for Planetary Geodesy at Technical University Berlin is developing routines for photogrammetric processing of planetary image data to derive 3D representations of planetary surfaces. The Integrated Software for Imagers and Spectrometers (ISIS) software (Anderson et al., 2004), developed by USGS, Flagstaff, is readily available, open source, and very well documented. Hence, ISIS was chosen as a prime processing platform and tool kit. However, ISIS does not provide a full photogrammetric stereo processing chain. Several components like image matching, bundle block adjustment (until recently) or digital terrain model (DTM) interpolation from 3D object points are missing. Our group aims to complete this photogrammetric stereo processing chain by implementing the missing components, taking advantage of already existing ISIS classes and functionality. We report here on the current status of the development of our stereo processing chain and its first application on the Lunar Apollo landing sites.

Macroautophagy is thought to protect against apoptosis; however, underlying mechanisms are poorly understood. We examined how autophagy affects canonical death receptor-induced mitochondrial outer membrane permeabilization (MOMP) and apoptosis. MOMP occurs at variable times in a population of cells, and this is delayed by autophagy. Additionally, autophagy leads to inefficient MOMP, after which some cells die through a slower process than typical apoptosis and, surprisingly, can recover and divide afterward. These effects are associated with p62/SQSTM1-dependent selective autophagy causing PUMA levels to be kept low through an indirect mechanism whereby autophagy affects constitutive levels of PUMA mRNA. PUMA depletion is sufficient to prevent the sensitization to apoptosis that occurs when autophagy is blocked. Autophagy can therefore control apoptosis via a key regulator that makes MOMP faster and more efficient, thus ensuring rapid completion of apoptosis. This identifies a molecular mechanism whereby cell-fate decisions can be determined by autophagy.

Programmed necrosis (or necroptosis) is a form of cell death triggered by the activation of receptor interacting protein kinase-3 (RIPK3). Several reports have implicated mitochondria and mitochondrial reactive oxygen species (ROS) generation as effectors of RIPK3-dependent cell death. Here, we directly test this idea by employing a method for the specific removal of mitochondria via mitophagy. Mitochondria-deficient cells were resistant to the mitochondrial pathway of apoptosis, but efficiently died via tumor necrosis factor (TNF)-induced, RIPK3-dependent programmed necrosis or as a result of direct oligomerization of RIPK3. Although the ROS scavenger butylated hydroxyanisole (BHA) delayed TNF-induced necroptosis, it had no effect on necroptosis induced by RIPK3 oligomerization. Furthermore, although TNF-induced ROS production was dependent on mitochondria, the inhibition of TNF-induced necroptosis by BHA was observed in mitochondria-depleted cells. Our data indicate that mitochondrial ROS production accompanies, but does not cause, RIPK3-dependent necroptotic cell death.

Caspase-8 or cellular FLICE-like inhibitor protein (cFLIP) deficiency leads to embryonic lethality in mice due to defects in endothelial tissues. Caspase-8−/− and receptor-interacting protein kinase-3 (RIPK3)−/−, but not cFLIP−/− and RIPK3−/−, double-knockout animals develop normally, indicating that caspase-8 antagonizes the lethal effects of RIPK3 during development. Here, we show that the acute deletion of caspase-8 in the gut of adult mice induces enterocyte death, disruption of tissue homeostasis, and inflammation, resulting in sepsis and mortality. Likewise, acute deletion of caspase-8 in a focal region of the skin induces local keratinocyte death, tissue disruption, and inflammation. Strikingly, RIPK3 ablation rescues both phenotypes. However, acute loss of cFLIP in the skin produces a similar phenotype that is not rescued by RIPK3 ablation. TNF neutralization protects from either acute loss of caspase-8 or cFLIP. These results demonstrate that caspase-8-mediated suppression of RIPK3-induced death is required not only during development but also for adult homeostasis. Furthermore, RIPK3-dependent inflammation is dispensable for the skin phenotype.

Patients with neurofibromatosis type 1 (NF1) and Costello syndrome Rasopathy have behavioral deficits. In NF1 patients, these may correlate with white matter enlargement and aberrant myelin. To model these features, we induced Nf1 loss or HRas hyperactivation in mouse oligodendrocytes. Enlarged brain white matter tracts correlated with myelin decompaction, downregulation of claudin-11, and mislocalization of connexin-32. Surprisingly, non-cell-autonomous defects in perivascular astrocytes and the blood-brain barrier (BBB) developed, implicating a soluble mediator. Nitric oxide (NO) can disrupt tight junctions and gap junctions, and NO and NO synthases (NOS1–NOS3) were upregulated in mutant white matter. Treating mice with the NOS inhibitor NG-nitro-L-arginine methyl ester or the antioxidant N-acetyl cysteine corrected cellular phenotypes. CNP-HRasG12V mice also displayed locomotor hyperactivity, which could be rescued by antioxidant treatment. We conclude that Nf1/Ras regulates oligodendrocyte NOS and that dysregulated NO signaling in oligodendrocytes can alter the surrounding vasculature. The data suggest that antioxidants may improve some behavioral deficits in Rasopathy patients.